The long-term objective of the proposed research is to understand the mechanism by which the mammalian nuclear transport machinery controls genomic organization and transcription in normal and cancer cells. The proposal will focus primarily on the nucleoporin Nup98 and the Ran GTPase exchange factor Red, since both proteins have been shown to associate with the genome. In addition, several Nup98 fusion proteins that result from chromosomal translocations are associated with some forms of leukemia. The Specific Aims of this proposal are to determine: 1) how the nuclear transport machinery interacts with the genome in mammalian cells, 2) how the interactions between Nup98, Red and the genome are affected by transcription, and 3) the mechanism of Nup98-mediated leukemogenesis. A combination of genome-wide location technology and expression profiling will be used to establish interactions between genomic loci and Nup98/Rcc1 in relation to the transcription status of those loci. The same approach will be used to determine alterations in the genomic occupancy of Nup98 fusion proteins associated with some forms of leukemia. This research will provide valuable insight into the aberrant pathways leading to these types of leukemia. [unreadable] [unreadable]